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Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer
Ferroptosis plays an important role in response to radiotherapy and chemotherapy, however, the sensitivity of cancer cell to ferroptosis varies. Here, the authors show that ODC1-mediated polyamine synthesis induces ferroptosis and demonstrate the potential of targeting this axis by combining polyamine supplements with radiotherapy or chemotherapy in preclinical lung cancer models.
- Guoshu Bi
- , Jiaqi Liang
- & Cheng Zhan
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| Open Access
Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability
MYC oncogene promotes tumourigenesis by coordinating cancer cell proliferation with metabolic adaptation to the consequent excessive oxidative stress. Here, the authors show that nudix hydrolase 1 (NUDT1) is a MYC-driven metabolic vulnerability and generate a NUDT1 protein degrader to treat preclinical MYC-associated cancer.
- Minhui Ye
- , Yingzhe Fang
- & Guoliang Qing
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Lactate dehydrogenase A regulates tumor-macrophage symbiosis to promote glioblastoma progression
Macrophage infiltration and metabolic rewiring are associated with glioblastoma. Here the authors show that the glycolytic enzyme lactate dehydrogenase-A mediates macrophage-cancer cell crosstalk to promote glioblastoma progression.
- Fatima Khan
- , Yiyun Lin
- & Peiwen Chen
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Filament formation drives catalysis by glutaminase enzymes important in cancer progression
Mitochondrial enzymes, collectively known as glutaminase, satisfy the metabolic requirements of cancer cells. Here the authors show that glutaminases form filamentous structures necessary for their catalytic activity.
- Shi Feng
- , Cody Aplin
- & Richard A. Cerione
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Inhibition of mitochondrial folate metabolism drives differentiation through mTORC1 mediated purine sensing
The role of folate metabolism in leukemic stem cells remains understudied. Here, the authors show that inhibition of mitochondrial folate metabolism leads to differentiation of leukemic cells through depletion of purines and suppression of mTORC1.
- Martha M. Zarou
- , Kevin M. Rattigan
- & G. Vignir Helgason
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The transcription factor ChREBP Orchestrates liver carcinogenesis by coordinating the PI3K/AKT signaling and cancer metabolism
Cancer cells adapt to changes in metabolism to ensure their survival. Here the authors show that glucose responsive transcription factor ChREBP reprograms liver cancer metabolism in part via enhancing the PI3K/AKT signaling.
- Emmanuel Benichou
- , Bolaji Seffou
- & Renaud Dentin
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Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial
MIND-DC was a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived natural dendritic cell (nDC)-based therapy in patients with stage III melanoma, showing that nDC-induced immune responses did not translate into survival benefit. Here the authors report that, despite randomization, baseline differences in fecal metagenomics and serum metabolomics profiles between treatment arms might have influenced the clinical outcome of the trial.
- Carolina Alves Costa Silva
- , Gianmarco Piccinno
- & I. Jolanda M. de Vries
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Metabolomic machine learning predictor for diagnosis and prognosis of gastric cancer
Gastric cancer detection by endoscopy is intrusive and time-consuming, and early detection is key to improving survival. Here, the authors propose a metabolite-based model to enable early detection.
- Yangzi Chen
- , Bohong Wang
- & Zeping Hu
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Unraveling the role of the mitochondrial one-carbon pathway in undifferentiated thyroid cancer by multi-omics analyses
Different types of metabolic rewiring are reported to drive cancer development and as a potential therapeutic target. Here, the authors perform multi-omics analyses in a cohort of human normal and malignant thyroid samples and show association of mitochondrial one-carbon metabolism with undifferentiated thyroid cancer.
- Seong Eun Lee
- , Seongyeol Park
- & Yea Eun Kang
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Caloric restriction leads to druggable LSD1-dependent cancer stem cells expansion
Caloric restriction (CR) has been demonstrated to have a role in tumour growth and therapy response but its effects on cancer stem cells are less known. Here, in Acute Promyelocytic Leukemia, the authors show that despite initial anti-tumour effect, CR drives the selection of leukaemia-initiating cells resulting in relapse which could be prevented by ablation of LSD1.
- Rani Pallavi
- , Elena Gatti
- & Pier Giuseppe Pelicci
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AKT1 phosphorylation of cytoplasmic ME2 induces a metabolic switch to glycolysis for tumorigenesis
The metabolic switch of tumours to aerobic glycolysis can allow them to meet their increasing energetic demands. Here, the authors show that AKT1 regulates this switch through the phosphorylation of malic enzyme 2 (ME2) preventing mitochondrial translocation. In turn this pushes the cell from mitochondrial metabolism to glycolysis, promoting tumour growth.
- Taiqi Chen
- , Siyi Xie
- & Wenjing Du
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Leukemia inhibitory factor suppresses hepatic de novo lipogenesis and induces cachexia in mice
Cancer cachexia is a systemic syndrome characterized by dramatic weight loss and decline in adipose tissue and skeletal muscle mass. Here, the authors show that overexpression of leukemia inhibitory factor (LIF), a secreted cytokine, suppresses de novo lipogenesis and induces cachexia in mice.
- Xue Yang
- , Jianming Wang
- & Wenwei Hu
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Niacin restriction with NAMPT-inhibition is synthetic lethal to neuroendocrine carcinoma
Nicotinamide phosphoribosyltransferase (NAMPT), a key enzyme for NAD synthesis, has been proposed as a potential target for cancer therapy. Here, the authors show synthetic lethality when combining NAMPT inhibition with Niacin restriction in neuroendocrine-type cancer.
- Miyuki Nomura
- , Mai Ohuchi
- & Nobuhiro Tanuma
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Enhanced SREBP2-driven cholesterol biosynthesis by PKCλ/ι deficiency in intestinal epithelial cells promotes aggressive serrated tumorigenesis
The underlying mechanisms driving colorectal cancer (CRC) through the serrated route are largely unknown. Here, the authors show that reduced aPKC levels increase cholesterol biosynthesis to promote aggressiveness in serrated tumours and targeting this pathway reduces tumourigenesis in preclinical models of serrated CRC.
- Yu Muta
- , Juan F. Linares
- & Jorge Moscat
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Itaconate promotes hepatocellular carcinoma progression by epigenetic induction of CD8+ T-cell exhaustion
Itaconate is an immunomodulatory metabolite that has been reported to regulate tumorigenesis. Here, the authors show that macrophage-derived itaconate induces epigenetic-mediated CD8+ T cell exhaustion, promoting hepatocellular carcinoma development.
- Xuemei Gu
- , Haoran Wei
- & Ping Gao
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Mirabegron displays anticancer effects by globally browning adipose tissues
Targeting metabolism is currently a promising approach for cancer treatment. Here, the authors show that the beta3 agonist mirabegron inhibits tumor progression by browning adipose tissues in preclinical murine models.
- Xiaoting Sun
- , Wenhai Sui
- & Yihai Cao
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SETD2 deficiency accelerates sphingomyelin accumulation and promotes the development of renal cancer
SET domain–containing 2 (SETD2) is reported as an immunosuppressor in clear cell renal cell carcinoma (ccRCC). Here the authors show that SETD2 loss enhances de novo sphingomyelin biosynthesis during the transition from polycystic kidney disease to ccRCC.
- Hanyu Rao
- , Changwei Liu
- & Xianting Ding
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Metabolic dependencies of metastasis-initiating cells in female breast cancer
Understanding the mechanisms associated with cancer metastasis may help control cancer progression. Here the authors investigate the metabolism of metastasis initiating cells in breast cancer and show that their metastatic ability relies on fatty acid oxidation and the oxidative tricarboxylic acid cycle, which in turn regulates acetyl-CoA generation and the acetylation of histones on EMT related genes.
- C. Megan Young
- , Laurent Beziaud
- & Joerg Huelsken
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Cyclic fasting bolsters cholesterol biosynthesis inhibitors’ anticancer activity
Nutritional stress induced by short-term dietary restriction has been shown to alter the activity of some anti-tumour drugs. Here, the authors demonstrate that periodic fasting enhances the anti-tumour effect of cholesterol biosynthesis inhibitors via decreased AKT-STAT3 signaling and oxidative phosphorylation.
- Amr Khalifa
- , Ana Guijarro
- & Alessio Nencioni
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Mutant p53 sustains serine-glycine synthesis and essential amino acids intake promoting breast cancer growth
Mutant p53 induces serine/glycine synthesis and essential amino acids intake. Under amino acid restriction, mutant p53 is stabilized and activates a transcriptional program that sustains a metabolic adaptive response promoting breast cancer cells growth
- Camilla Tombari
- , Alessandro Zannini
- & Giannino Del Sal
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Palmitoylation-driven PHF2 ubiquitination remodels lipid metabolism through the SREBP1c axis in hepatocellular carcinoma
Palmitoylation of proteins can have pathophysiological implications. Here, the authors show that palmitoylation enhances the proteasomal degradation of the histone demethylase PHF2, leading to increased lipogenesis and cell proliferation in an SREBP1c dependent manner and further show that PHF2 acts as an E3 ligase of SREBP1c, suppressing the growth of liver cancer cells.
- Do-Won Jeong
- , Jong-Wan Park
- & Yang-Sook Chun
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Positive regulation of oxidative phosphorylation by nuclear myosin 1 protects cells from metabolic reprogramming and tumorigenesis in mice
Metabolic reprogramming is a hallmark of tumorigenesis. Here, the authors show that nuclear myosin 1 regulates mitochondrial oxidative phosphorylation via the TFAM and PGC1α transcription factors and suggest its depletion contributes to the Warburg effect during tumorigenesis.
- Tomas Venit
- , Oscar Sapkota
- & Piergiorgio Percipalle
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Decreased liver B vitamin-related enzymes as a metabolic hallmark of cancer cachexia
Cancer cachexia is a multifactorial metabolic syndrome affecting a large fraction of patients with advanced cancer. Here the authors report a decrease in B vitamin-related liver enzymes in mouse models and gastric cancer patients with cachexia.
- Yasushi Kojima
- , Emi Mishiro-Sato
- & Masahiro Aoki
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The lipoprotein-associated phospholipase A2 inhibitor Darapladib sensitises cancer cells to ferroptosis by remodelling lipid metabolism
Ferroptosis is an iron-dependent cell death mechanism that is emerging as a target for cancer therapy. Here, the authors find that lipoprotein-associated phospholipase A2 modulates ferroptosis resistance by controlling phospholipid metabolism.
- Mihee Oh
- , Seo Young Jang
- & Eun-Woo Lee
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Fasting mimicking diet in mice delays cancer growth and reduces immunotherapy-associated cardiovascular and systemic side effects
The use of immune checkpoint inhibitors is associated with a wide range of side effects. Here the authors explore the use of periodic cycles of a diet that mimics fasting and see reduction in side effects caused by a range of immune checkpoint blockade antibodies in a preclinical cancer model.
- S. Cortellino
- , V. Quagliariello
- & V. D. Longo
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AhR diminishes the efficacy of chemotherapy via suppressing STING dependent type-I interferon in bladder cancer
An effective response to chemotherapy is often associated with the promotion of type-I interferons and anti-tumor immune responses. Here the authors show that tryptophan metabolites induced by chemo-drugs interfere with STING activation and IFN-I production in bladder cancer, reducing the efficacy of chemotherapy.
- Zikun Ma
- , Zhiyong Li
- & Xiaoyu Liang
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Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis
The molecular mechanisms underlying the transformation of Chronic Myeloid Leukaemia (CML) from chronic phase (CP) to blast crisis (BC) are not completely elucidated. Here, the authors show that acquired miR-142 deficiency drives CML BC by regulating mitochondrial metabolism and is a potential therapeutic target to prevent BC in CML murine models.
- Bin Zhang
- , Dandan Zhao
- & Guido Marcucci
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REPTOR and CREBRF encode key regulators of muscle energy metabolism
Obesity and cancer-induced cachexia are linked to an impairment in the ability of muscle to use glucose or lipids interchangeably as energy substrates. Here, the authors propose that Drosophila REPTOR and its mammalian ortholog CREBRF act as key transcriptional regulators of fuel choice in muscle.
- Pedro Saavedra
- , Phillip A. Dumesic
- & Norbert Perrimon
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Characterizing cancer metabolism from bulk and single-cell RNA-seq data using METAFlux
Metabolic reprogramming is a common indicator of the tumour microenvironment. Here the authors develop the METAflux framework to predict metabolic fluxes from single cell RNA-seq data.
- Yuefan Huang
- , Vakul Mohanty
- & Ken Chen
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A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis
Cholesterol synthesis is highly oxygen consuming but how it is regulated by oxygen levels has not been clear. Here, Dickson et al. identify a HIF-independent, oxygen-sensing pathway for controlling cholesterol synthesis in human cells involving hypoxic-mediated degradation of SREBP2.
- Anna S. Dickson
- , Tekle Pauzaite
- & James A. Nathan
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Intermittent dietary methionine deprivation facilitates tumoral ferroptosis and synergizes with checkpoint blockade
The application of dietary methionine intervention is of particular interest in the field of cancer therapy. Here the authors show that intermittent but not sustained deprivation of methionine promotes tumor ferroptosis and improves response to checkpoint inhibitors.
- Ying Xue
- , Fujia Lu
- & Weimin Wang
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Targeting of SLC25A22 boosts the immunotherapeutic response in KRAS-mutant colorectal cancer
KRAS mutations are associated with an immunosuppressive microenvironment in patients with colorectal cancer (CRC). Here the authors show that knockout of SLC25A22, a mitochondrial glutamate carrier, reverts KRAS-mediated immunosuppression in preclinical CRC models, by suppressing CXCL1 production and impairing MDSC recruitment.
- Qiming Zhou
- , Yao Peng
- & Chi Chun Wong
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A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses
Metabolic pressure, in particular the lack of methionine availability, on tumor-infiltrating CD8 + T cells is associated with T cell dysfunction. Since tumor cells rely on SLC43A2 for methionine uptake, here the authors design a nanoplatform for CRISPR/Cas9 mediated silencing of SLC43A2 and STING activation, restoring anti-tumor T cell immune responses.
- Ying Huang
- , Geng Qin
- & Xiaogang Qu
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Oncolytic viruses engineered to enforce cholesterol efflux restore tumor-associated macrophage phagocytosis and anti-tumor immunity in glioblastoma
Glioblastoma (GBM) cells are metabolically dependent on exogenous cholesterol uptake and targeting cholesterol metabolism has been proposed as a therapeutic option for GBM. Here the authors show that cholesterol promotes phagocytic dysfunction in tumor associated macrophages and they develop an Apo-A1 armed oncolytic adenovirus restoring anti-tumor immunity in GBM preclinical models.
- Wang Shiqun
- , Yan Wei
- & Wei Jiwu
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Oxidative phosphorylation is a metabolic vulnerability of endocrine therapy and palbociclib resistant metastatic breast cancers
Patients with estrogen receptor positive breast cancer (ER + BC) treated with palbociclib (CDK4/6 inhibitor) frequently develop resistance. Here, the authors identify a reliance of palbociclib resistance on oxidative phosphorylation (OXPHOS) and therapeutically target this vulnerability using an OXPHOS inhibitor, restoring sensitivity in ER + BC preclinical models.
- Rania El-Botty
- , Ludivine Morriset
- & Elisabetta Marangoni
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ACTL6A protects gastric cancer cells against ferroptosis through induction of glutathione synthesis
Diagnostic markers and therapeutic targets for gastric cancer are in urgent need. Here, the authors 2 find elevated expression of ACTL6A in gastric cancer promotes glutathione synthesis by regulating 3 GCLC expression to suppress ferroptosis.
- Ziqing Yang
- , Shaomin Zou
- & Lekun Fang
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Increased glucose availability sensitizes pancreatic cancer to chemotherapy
Response to chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) is often limited. Here, the authors report improved response to chemotherapy in PDAC patients with hyperglycaemia and investigate the underlying mechanism via glucose-mediated disruption of redox metabolism
- Ali Vaziri-Gohar
- , Jonathan J. Hue
- & Jordan M. Winter
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| Open Access
SLC7A11 expression level dictates differential responses to oxidative stress in cancer cells
The cystine transporter SLC7A11 protects cancer cells from oxidative stress by supporting glutathione synthesis. Here, the authors show that the expression level of SLC7A11 leads to different outcomes depending on context, so high expression promotes primary tumour growth but promotes disulfide stress under oxidative stress conditions and impairs metastasis.
- Yuelong Yan
- , Hongqi Teng
- & Boyi Gan
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| Open Access
Transcriptional control of pancreatic cancer immunosuppression by metabolic enzyme CD73 in a tumor-autonomous and -autocrine manner
Expression of the metabolic enzyme CD73 has been associated with immunosuppression in cancer. Here the authors show that tumor cell-autonomous CD73 promotes regulatory T-cell accumulation and that CD73 targeting sensitizes pancreatic cancer to PD-1 blockade.
- Tianyu Tang
- , Xing Huang
- & Tingbo Liang
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Article
| Open Access
Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity
Lysophosphatidic acid is known to increase in concentration in multiple cancer types. Here, the authors show it affects CD8 T cell metabolism, phenotype, and effector functions, and plasma concentrations appear predictive of response to immunotherapy.
- Jacqueline A. Turner
- , Malia A. Fredrickson
- & Raul M. Torres
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| Open Access
AMPK is a mechano-metabolic sensor linking cell adhesion and mitochondrial dynamics to Myosin-dependent cell migration
Cell metabolism must adapt to the energy needs of migrating cells. This study finds that fast amoeboid migrating cells harbor high AMPK activity, which controls both mitochondrial dynamics and cytoskeletal remodeling, enabling reduced energy needs.
- Eva Crosas-Molist
- , Vittoria Graziani
- & Victoria Sanz-Moreno
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| Open Access
Alanine supplementation exploits glutamine dependency induced by SMARCA4/2-loss
Cancers with concomitant SMARCA4/2 deficiencies are often resistant to chemotherapies and confer a poor prognosis. Here, the authors identify a metabolic dependency of these tumours on glutamine as an energy source and, using multiple approaches, demonstrate the efficacy of therapeutically targeting this vulnerability.
- Xianbing Zhu
- , Zheng Fu
- & Sidong Huang
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| Open Access
Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer
The spatial signature of metabolic remodeling in tumours remains to be explored. Here, the integration of mass spectrometry imaging-based spatial metabolomics and lipidomics with microarray-based spatial transcriptomics allows the visualisation of metabolic heterogeneity in gastric cancer.
- Chenglong Sun
- , Anqiang Wang
- & Jiuming He
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Article
| Open Access
Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells
The deprivation of amino acids in the tumor microenvironment affects T cell survival and activation. Here the authors show that reduced levels of methionine are associated with PD1 upregulation in CD4+ T cells and that methionine supplementation promotes CD4+ T cell dependent anti-tumor immune responses.
- Mahesh Pandit
- , Yun-Seo Kil
- & Jae-Hoon Chang
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| Open Access
Metabolism-based targeting of MYC via MPC-SOD2 axis-mediated oxidation promotes cellular differentiation in group 3 medulloblastoma
The molecular mechanisms underlying MYC overexpression in group 3 medulloblastoma remain to be explored. Here, the authors highlight the involvement of the mitochondrial pyruvate carrier- SOD2 signalling pathway in the regulation of MYC protein abundance.
- Emma Martell
- , Helgi Kuzmychova
- & Tanveer Sharif
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| Open Access
Ether phospholipids are required for mitochondrial reactive oxygen species homeostasis
Cancer cells can be dependent on mitochondrial respiration to survive. Here, in pancreatic cancer cells, the authors show that monounsaturated fatty acids-linked ether lipids maintain mitochondrial redox homeostasis and modulate sensitivity to inhibition to electron transport chain complex I.
- Ziheng Chen
- , I-Lin Ho
- & Haoqiang Ying
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| Open Access
Mannose metabolism inhibition sensitizes acute myeloid leukaemia cells to therapy by driving ferroptotic cell death
Metabolic rewiring is involved in acute myeloid leukaemia (AML) maintenance. Here the authors show that the inhibition of mannose-6-phosphate isomerase in the mannose metabolism pathway sensitizes AML to FLT3-tyrosine kinase inhibitor and standard chemotherapy via enhancing lipid peroxidation and ferroptotic cell death.
- Keith Woodley
- , Laura S. Dillingh
- & Paolo Gallipoli
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| Open Access
Quinolinate promotes macrophage-induced immune tolerance in glioblastoma through the NMDAR/PPARγ signaling axis
The upstream metabolism of tryptophan has been described as a metabolic node in glioblastoma. Here the authors show that the downstream metabolism of tryptophan, resulting in the accumulation of quinolinate in glioblastoma, contributes to pro-tumorigenic immune suppressive activation of macrophages.
- Pravin Kesarwani
- , Shiva Kant
- & Prakash Chinnaiyan
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Article
| Open Access
Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism
Diet intervention is emerging as an option to improve cancer therapy. Here, the authors show that a diet with restrictive cysteine and methionine synergizes with a ferroptosis inducer to increase cell death and survival in glioma preclinical models.
- Pavan S. Upadhyayula
- , Dominique M. Higgins
- & Peter Canoll
Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies